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INDIAN DENTAL ACADEMY
Leader in continuing Dental Education
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Chemical mediators / dental implant courses

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The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.


The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.

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Chemical mediators / dental implant courses

  1. 1. INDIAN DENTAL ACADEMY Leader in continuing Dental Education www.indiandentalacademy.com
  2. 2. Inflammation is defined as a complex reaction to injurious agents such as microbes and damaged, usually necrotic, cells that consists of vascular responses, migration and activation of leukocytes, and systemic reactions www.indiandentalacademy.com
  3. 3.  3000 BC – signs of inflammation described by PAPYRUS ( Egyptian)  1st AD – CELSUS, roman writer listed 4 Cardinal signs RUBOR - redness TUMOR - swelling CALOR - heat DOLOR - pain  VIRCHOW – added 5th Cardinal sign FUNCTIOLAESA - loss of function www.indiandentalacademy.com
  4. 4.  1793 – JOHN HUNTER (Scottish) – it is not a disease, but non specific response, which has salutary effect on its Host  1839 – 1884 – JOHN COHNHEIN observed Inflamed blood vessels (frogs) – Increased vascular permeability and Leukocyte emigration www.indiandentalacademy.com
  5. 5.  1882 – ELIE METCHNIKOFF (Russian) observed PHAGOCYTOSIS . Purpose of inflammation is to get phagocytes in injured area to engulf the bacteria  Same time –– PAUL EHLICH Neutralize the infectious agent by serum factors ( antibodies)  1908 – METCHNIKOFF and PAUL EHLICH got NOBLE prize for their work.  Both PHOGOCYTES (CELLULAR) and SERUM FACTORS ( ANTIBODIES) are responsible to defense against MICROBES www.indiandentalacademy.com
  6. 6. The Triple Response:  SIR THOMAS LEWIS (1927), established the Concept that Histamine locally induced by injury mediate the vascular changes;  This concept underlies the use of anti- Inflammatory agents in clinical medicine.  Firmly stroking the fore arm with a Blunt instrument, evokes this response.  Within one min. a red line appears; (because of dilatation of arterioles, capillaries & venules).  A red flare develops (because of vasodilation of the tissue surrounding injury);  A wheal forms because of exudation fluid  The flare, which is a minor component is mediated by local axon reflex; www.indiandentalacademy.com
  7. 7.  The major components, red line & wheal were shown to be independent of neural connections www.indiandentalacademy.com
  8. 8.  Unique feature of the inflammatory process is the reaction of blood vessels, leading to the accumulation of fluid and leukocytes in extravascular tissues.  The inflammatory response is closely intertwined with the process of repair.  Inflammation serves to destroy, dilute, or walloff the injurious agent, and it sets into motion a series of events that try to heal and reconstitute the damaged tissue www.indiandentalacademy.com
  9. 9.  Inflammatory response consists of two main components 1. Vascular Events 2. Cellular Events www.indiandentalacademy.com
  10. 10.  Many tissues and cells are involved in these reactions, including the fluid and proteins of plasma, circulating cells, blood vessels, cellular and extracellular constituents of connective tissue. www.indiandentalacademy.com
  11. 11.  Inflammation is divided into 1. Acute Inflammation 2. Chronic Inflammation www.indiandentalacademy.com
  12. 12.  Rapid in onset (Seconds or Minutes)  Short duration  Lasting for minutes to several hours or a few days  Exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils www.indiandentalacademy.com
  13. 13.  Longer duration and  Associated histologically with the presence of lymphocytes and macrophages, the proliferation of blood vessels, fibrosis and tissue necrosis. www.indiandentalacademy.com
  14. 14.  Stimuli for Acute inflammation  Trauma  Physical and chemical agents  Tissue necrosis  Foreign bodies  Immune reactions  Infection www.indiandentalacademy.com
  15. 15. Acute Inflammation  Alteration in vascular caliber  Structural changes in the microvasculature  Emigration of the leukocytes from the microcirculation www.indiandentalacademy.com
  16. 16. Vascular changes:  Change in vascular flow and caliber  Increased vascular permeability(vascular leakage) www.indiandentalacademy.com
  17. 17. Change in vascular flow & caliber: www.indiandentalacademy.com
  18. 18. Increased vascular permeability:  Formation of Endothelial gaps in Venules  Direct endothelial injury  Delayed prolonged leakage  Leukocyte – mediated endothelial injury  Increased transcytosis  Leakage from new blood vessels www.indiandentalacademy.com
  19. 19. www.indiandentalacademy.com
  20. 20. Cellular Events  Neutrophils form the first line of defence;  The multi step process of leucocyte migration: - Neutrophils first roll, - Then become activated, - Adhere to endothelium, - Transmigrate along the endothelium, - Pierce the Basement membrane - Migrate toward the chemoattractants - Emanating from the source of injury. www.indiandentalacademy.com
  21. 21. Molecules that play predominent role in each step:  SELECTINS:- E-Selectin &P-Selectin; In rolling (tumbling along the endothelium)  CHEMOKINES: Act on the rolling cells & activate them. Activation results from several signaling Pathways that result in increase in cytosolic Ca++,& activation of enzymes such as Protein kinase C & Phospholipase A2.  INTEGRINS: (Beta 1 & Beta2 ) In firm adhesion;Integrin superfamily Consisting of 30 proteins,that promote Cell to cell or cell to matrix inter action. They coordinate signals with cytoskeleton dependent motility, Phagocytic response ect. www.indiandentalacademy.com
  22. 22.  CD 31 (PECAM-1)- Adhesion molecule in trans- migration, Leukocyte migration occurs predominantly. In venules; they pierce the BM by Secreting collagenases. www.indiandentalacademy.com
  23. 23. www.indiandentalacademy.com
  24. 24. Importance Of Adhesion Molecules: Genetic defects in adhesion molecules result in  Recurrent bacterial infections;  LAD-Type-I- have defect in biosynthesis of Beta chain;  LAD-TYPE-2-have defects in Fucosyl transferase enzyme ; www.indiandentalacademy.com
  25. 25. LAD-I (CD11/CD18 Deficiency):  Rare; inherited disorder; Detected in early childhood; delayed umbilical cord separation may be Life threatening. Infections of middle ear, oropharynx ect.  Neutrophils roll, but do not adhere or migrate. LAD-2:  Short stature &distinct facial appearance;  Recurrent bacterial infections—including Pneumonias, cellulitis without pus & Periodontitis  Surface CD18 expression is normal;  Lack of CD15 expression seen;  Neutrophils do not roll on endothelial Cells, & do not adhere www.indiandentalacademy.com
  26. 26. Emigrating Leukocytes:  Varies with the age of the response & With the type of stimulus;  In most forms, Neutrophils predominate during the first 6-24 hrs;  After entering the tissue, they undergo Apoptosis & disappear; In certain infections (Eg. Pseudomonas inf.), they predominate over 2-4 days;  In viral inf. lymphocytes are the first cells to arrive. www.indiandentalacademy.com
  27. 27.  Chemotaxis Defined as locomotion oriented along a Chemical gradient.  All granulocytes, monocytes, & to a lesser extent lymphocytes respond to stimuli with varying rates of speed.  Exogenous agents- bacterial products,  Endogenous- 1.C5a, 2.Leucotriene (LTB4) 3. Cytokine (IL-8). www.indiandentalacademy.com
  28. 28. Defects In Chemotaxis:  Localised Juvenile Periodontitis: Is characterised by alveolar bone loss, most prominently of the incisors & first Molars.  They don’t have extra oral infections;  Abnormal Chemotaxis to FMLP & C5a has been reported; Neutrophils in these Pts express CR2 on surface in contrast to control cells;  Normally, CR2 is present only on immature cells & lost during Maturation, before release from the marrow. www.indiandentalacademy.com
  29. 29. Leukocyte Activation:  Results from several signals passing through & trigger leucocytes; result in Increase in cytosolic Ca++ & activates Enzymes such as Protein kinase C & Phospholipase A2;  As a result the following responses occur; 1 Production of AA metabolites from Phospholipids; 2 Degranulation & secretion of lysosomal enzymes & activation of Oxidative Burst. 3 Secretion of Cytokines which amplify & Regulate inflammatory reactions; 4 Modulation of adhesion molecules allowing firm adhesion of activated Neutrophils to the endothelium. www.indiandentalacademy.com
  30. 30.  Neutrophils express a no. of surface receptors involved in the activation: 1. Toll like receptors (TLRs) (which play a role in adhesion & response to LPS) 2. 7mem Gprotein receptors (recognize chemokines,C5a,PAF,LTB4 &Prosta.E) www.indiandentalacademy.com
  31. 31.  Neutrophils www.indiandentalacademy.com
  32. 32. Phagocytosis (Cell Eating):  When a neutrophil meets a particle, it envelops it with pseudopodia which flow around it forming a phagolysosome that rapidly fuse with Azurophilic & Specific granules. Granule Release:  Neutrophil contains 4 types of intracellular Granules: Azurophilic,specific, Gelatinase(Tertiary)& Sec.Ves. www.indiandentalacademy.com
  33. 33. www.indiandentalacademy.com
  34. 34. www.indiandentalacademy.com
  35. 35. Oxygen dependent mechanisms  Free O2 radicals:  Phagocytosis initiates HMP shunt; causing a burst in O2 consumtion, glucose oxidation & Production of reactive O2 metabolites;  O2 is reduced to Superoxide ion which is then converted to H2O2 by spontaneous dismutation.  This H2O2 is not powerful bactericidal. www.indiandentalacademy.com
  36. 36.  Production of reactive O2 Species www.indiandentalacademy.com
  37. 37. O2 Independent Mechanisms  LYSOZYME-in neutrophil granules can lyse the cellwall of some bacteria, -gram +ve cocci;  Lactoferrin-a protein that binds Iron &inhibits bacterial growth by depriving them of it;  BPI-Bactericidal permeability increasing factor.  Elastase (found in granules)  Defensins Ect.contribute for killing the bacteria. www.indiandentalacademy.com
  38. 38. Mediators originate from either –  Plasma – e.g. complement proteins & kinins - These are present in precursor forms that must be activated by series of proteolytic cleavage → acquire biologic properties  Cells – present in intracellular granules that need to be secreted (e.g. Histamine in mast cells) or synthesized denovo in response to stimulus (e.g. Prostaglandins, cytokines) www.indiandentalacademy.com
  39. 39. www.indiandentalacademy.com
  40. 40. Mediators perform activity by –  Mostly by binding to receptors on target cells  Direct enzymatic activity e.g. Lysosomal proteases  Mediate oxidative damage e.g. reactive oxygen species & nitrogen intermediates Mediators can act on –  One or few target cells Can have diverse targets  Have different effect on different cell types www.indiandentalacademy.com
  41. 41.  Once activated & released from the cell the mediators are short lived. They either –  Quickly decay e.g. Arachidonic acid metabolites  Inactivated by enzymes e.g. kininase inactivates Bradykinin  Scavenged e.g. antioxidants scavenge toxic oxygen metabolites  Inhibited e.g. complement regulatory proteins breakup & degrade activated complement components www.indiandentalacademy.com
  42. 42. Vasoactive amines:  First mediators to be released during inflammation are- Histamine Serotonin www.indiandentalacademy.com
  43. 43. Histamine:  Richest source –mast cells -also in platelets & Basophils Stimuli for degranulation of Mast cells –  Physical injury such as trauma , cold or heat  Immune reactions involving binding of antibodies to Mast cells  Fragments of complement called Anaphylotoxins (C3a & C5a )  Neuropeptides (substance P )  Cytokines (IL – 1 & IL – 8 ) www.indiandentalacademy.com
  44. 44. Action of Histamine  Dilation of arterioles ( but constriction of large arterioles )  Increased permeability of venules  Principle mediator of immediate transient phase of increased vascular permeability  Acts on microcirculation mainly via binding to H1 receptor on endothelial cells www.indiandentalacademy.com
  45. 45. Serotonin:  Action similar to that Histamine  Source – platelets & Enterochromaffin cells  Release from platelets occurs when platelets aggregate after contact with – Collagen Thrombin ADP Ag- Ab complexes www.indiandentalacademy.com
  46. 46.  Plasma proteins that mediate inflammatory response belong to 4 interrelated systems  Complement system  Kinin system  Clotting system  Fibrinolytic www.indiandentalacademy.com
  47. 47. Complement system-  Complement system consists of 20 component proteins that are found in greatest concentration in plasma Complement components causes –  Increasing vascular permeability  Chemotaxis  Opsonisation Activation of complement cascade consists of 2 steps i.e. early step & late step  Early steps consists of 3 different pathways & lead to proteolytic cleavage of C3  Late steps – all 3 pathways converge & major breakdown products of C3, C3b activate a series of other complement components www.indiandentalacademy.com
  48. 48.  The early steps in complement activation consists of 3 pathways i.e. – Classical pathway Alternate pathway Lectin pathway www.indiandentalacademy.com
  49. 49.  classical pathway www.indiandentalacademy.com
  50. 50.  Alternate pathway www.indiandentalacademy.com
  51. 51.  Lectin pathway www.indiandentalacademy.com
  52. 52.  PLASMA PROTEINS Late pathway www.indiandentalacademy.com
  53. 53. www.indiandentalacademy.com
  54. 54. PLASMA PROTEINS Regulation of complement activation  Regulation of C3 & C5 convertase by enhancing dissociation of convertase complex e.g. Decay accelerating factor  Binding of active complement components by specific proteins in plasma  C1 inhibitor interferes with enzymatic activity of C1  Proteins that inhibit MAC formation e.g. CD59 inhibit excessive complement activation www.indiandentalacademy.com
  55. 55. The biologic function of complement system  Cell lysis by MAC  Vascular phenomenon – increased vascular permeability & vasodilatation  Leukocyte adhesion, chemotaxis & activation  Phagocytosis www.indiandentalacademy.com
  56. 56. Disorders of complement system  Deficiency of complement components lead to increased susceptibility to infections  Deficiency of C4 & C2 – autoimmune diseases e.g. SLE  Genetic defeciency of complementary regulatory protein – significant disease – e.g. Paroxysmal Nocturnal Hematuria  Defeciency of C1 inhibitor – Hereditory angioneurotic edema www.indiandentalacademy.com
  57. 57.  Kinin & Clotting system www.indiandentalacademy.com
  58. 58. www.indiandentalacademy.com
  59. 59. Protease activated receptors  These are 7- Transmembrane G – protein receptors present on platelets, endothelial cells, smooth muscle cells, etc.  Engagement of PAR by proteases particularly Thrombin triggers several responses like-  Mobilization of P- selectin  Production of chemokines  Expression of endothelial adhesion molecule  Production of Prostaglandins, PAF, & NO  Changes in endothelial shape www.indiandentalacademy.com
  60. 60. ARACHIDONIC ACID METABOLITES Membrane lipids ↓ Biologically active lipid products (Autocoids – short range of hormones- formed rapidly – exert their effects locally – either decay spontaneously or destroyed enzymatically ) ↓ Serve as extracellular or intracellular signals to affect variety of biologic process including inflammation & hemostasis www.indiandentalacademy.com
  61. 61. Cell membrane phospholipids ↓ phospholipases Dietary sources → Arachidonic acid ↓ Cyclooxygenase Lipooxygenase Eicosanoids www.indiandentalacademy.com
  62. 62.  Eicosanoids + G-protein coupled receptors on various cell types – mediate steps of inflammation www.indiandentalacademy.com
  63. 63. LIPOXINS  Lipoxins are generated by transcellular biosynthetic mechanisms involving two cell population  Leukocytes produce intermediates in Lipoxin synthesis which are converted to Lipoxin by platelets interacting with leukocytes www.indiandentalacademy.com
  64. 64.  Biosynthesis of Leukotrienes & Lipoxins www.indiandentalacademy.com
  65. 65. The principle action of Lipoxins are –  Inhibit leukocyte recruitment & cellular components of inflammation  Inhibit neutrophil chemotaxis & adhesion to endothelium  Lipoxins may be endogenous negative regulators of Leukotrienes leading to resolution of inflammation www.indiandentalacademy.com
  66. 66.  Anti inflammatory therapy can be directed at many targets along the Eicosanoids biosynthetic pathway  Cyclooxygenase inhibitors – (COX 1, COX 2) e.g. NSAIDS like Indomethacin inhibit Prostaglandin synthesis by irreversibly acetylating & inhibiting Cyclooxygenase  Lipoxygenase pathway – used in treatment of Asthma  Broad spectrum inhibitors – e.g. Glucocorticoids. They act by down regulating the expression of genes like genes encoding for COX2, Phospholipase A2, NO synthetase e.t.c. They also up regulate the genes encoding for anti-inflammatory proteins like Lipocortin-1 www.indiandentalacademy.com
  67. 67. PLATELET ACTIVATING FACTORS  PAF is bioactive phospholipid derived mediators  PAF is derived from antigen stimulated IgE sensitized Basophils that cause platelet aggregation Sources – Neutrophils, Platelets, Basophils, Mast cells, Endothelial cells. www.indiandentalacademy.com
  68. 68. Functions –  Platelet stimulation  Vasoconstriction ( in low conc. It induces vasodilatation & increased venular permeability)  Increased leukocyte adhesion to endothelium  Chemotaxis  Degranulation  Increased synthesis of other mediators by leukocytes & other cells www.indiandentalacademy.com
  69. 69. CYTOKINES & CHEMOKINES  Cytokines are proteins produced by many cell types principally activated Lymphocytes, Macrophages, Endothelium, Epithelium & Connective tissue cells www.indiandentalacademy.com
  70. 70. TUMOR NECROSIS FACTOR & INTERLEUKIN-1  They are produced mainly by activated macrophages & they mediate inflammation  Secretion of TNF & IL-1 is stimulated by – endotoxins, microbial products, immune complexes, physical injury e.t.c. Functions –  Effects on Endothelium, leucocytes, & fibroblast  Induction of systemic & acute phase reactants www.indiandentalacademy.com
  71. 71. ENDOTHELIAL EFFECTS  Increased synthesis of endothelial adhesion molecules & chemical mediators like cytokines, chemokines, growth factors, eicosanoids & NO.  Production of enzymes associated with matrix remodeling  Increase in the surface thrombogenecity of the endothelium  Increased procoagulant activity, Decrease in anticoagulant activity www.indiandentalacademy.com
  72. 72. EFFECTS ON FIBROBLAST  Increased proliferation  Increased collagen synthesis  Increased collagenase  Increased protease  Increased PGE synthesis www.indiandentalacademy.com
  73. 73. LEUKOCYTE EFFECT  Increased cytokine secretion ( IL-1, IL-6 ) IL-1 & TNF induces systemic acute phase response which include-  Fever  Loss of appetite  Release of Neutrophils into circulation  Hemodynamic effects like hypotension, decreased vascular resistance, increased heart rate e.t.c.  Regulates body mass by regulating lipid & protein mobilization & by suppressing appetite www.indiandentalacademy.com
  74. 74. CHEMOKINES  Chemokines are a family of small proteins that act primarily as chemoattractant  They are classified into 4 major groups based on the arrangement of conserved cysteine residues in the mature proteins  C-X-C chemokines (Alpha chemokine)  C-C chemokines (Beta chemokines)  C chemokines (Gamma chemokines)  CX,C chemokines  www.indiandentalacademy.com
  75. 75.  NITRIC OXIDE www.indiandentalacademy.com
  76. 76. LYSOSOMAL CONSTITUENTS OF LEUKOCYTES  Neutrophils & monocytes contain granules that produce inflammatory response  Neutrophils contain 2 main types of granules-  Small specific granules  Large Azurophilic granules www.indiandentalacademy.com
  77. 77. Smaller specific granules contain  Collagenase  Gelatinase  Lactoferrin  Plasminogen activator  Histaminase  Alkaline phosphatase  Phospholipase A2 Large Azurophilic granules contain  Myeloperoxidase  Bactericidal factors (lysozyme, defensins)  Acid hydrolases  Variety of neutral proteases (Elastases, Cathepsin G, Non- specific collagenase, proteinase – 3 )  Phospholipase A2  Bacterial permeability increasing protein(BPI) www.indiandentalacademy.com
  78. 78. OTHER MEDIATORS  Hypoxia induced factor 1 alpha  Uric acid which is break down product of DNA in necrotic cells www.indiandentalacademy.com
  79. 79. Applied Anatomy www.indiandentalacademy.com
  80. 80.  Acute inflammation-Morphology 1. Pseudomembranous inflammation  It is the response of mucous membrane (Oral, respiratory, bowel) to toxins of the diphtheria, or irritant gases. Due to denudation of epithelium, plasma exudes on the surface, where it coagulates & together with Necrosed epithelium, forms false membrane that gives the name. www.indiandentalacademy.com
  81. 81. 2. Ulcer  Ulcers are local defects on surface of an organ produced by inflammation, i.e. discontinuity of the lining epithelium.  Common sites are stomach, intestines(e.g. Typhoid fever), intestinal Tuberculosis, Bacillary & Amoebic dysentery etc.  Ulcers of legs due to Varicose veins.  May be acute or chronic www.indiandentalacademy.com
  82. 82. 3.Abscess formation (Suppuration-Purulent inflammation)  Abscesses are focal collections of pulse that may be caused by deep seeding of Pyogenic organisms or by secondary infection of necrotic foci. They have a central necrotic region rimmed by a layer of preserved neutrophils with a zone of dilated vessels & Fibroblastic proliferation. Abscess  The purulent exudate or pus is creamy & or opaque in appearance & is composed of numerous dead as well as living neutrophils, red cells, tissue debris & fibrin.  In old pus macrophages & Cholesterol crystals may be present.  It may discharge to the surface due to increased pressure inside or may require drainage. www.indiandentalacademy.com
  83. 83. 4.Cellulitis  It is a diffused inflammation of soft tissues resulting from spreading effects of substances like Hyaluronidase released by some bacteria. www.indiandentalacademy.com
  84. 84. Fate of acute inflammation  Acute inflammatory process can result in one of the following outcomes 1.Resolution 2.Healing by scarring 3.Progression to suppuration 4.Progression to chronic inflammation. www.indiandentalacademy.com
  85. 85. Resolution  It means complete return to normal tissue following acute inflammation.  This occurs when the injury is limited or with minimal tissue damage & when the tissue is capable of replacing the injured cells. E.g Resolution in Lobar Pneumonia www.indiandentalacademy.com
  86. 86. Healing by Scarring  This takes place when the tissue destruction is extensive; there is no regeneration, extensive fibrinous exudate occurs which cannot be completely absorbed.  There is healing by Fibrosis. E.g Healing of Abscess(In certain bacteria or fungal infections due to Pyogenic infections) www.indiandentalacademy.com
  87. 87. Progression to Suppuration  When Pyogenic bacteria cause acute inflammation resulting in severe tissue necrosis, Suppuration sets in.  Initially, there is intense neutrophilic infiltration. Subsequently mixture of neutrophils, bacteria, fragments of Necrotic tissue, cell debris & Fibrin comprise “pus” which is contained in a cavity forming an Abscess. If it is not drained, it may get organised & in time get calcified. www.indiandentalacademy.com
  88. 88. Progression to Chronic inflammation  Acute inflammation may progress to chronic inflammation in which the process of inflammation & healing proceed side by side.  Depending on the extent of initial injury & the capacity of the tissue, there may be regeneration or Scarring. www.indiandentalacademy.com
  89. 89. THANK YOU www.indiandentalacademy.com

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